N-benzyl-N-{8 2-phenyl-2-(4-phenyl-1-piperidyl)ethyl{9 {0 propionamide para-chlorobenzene sulfonate

ABSTRACT

N-benzyl-N-(2-phenyl-2-(4-phenyl-1-piperidyl)ethyl) propionamide p-chlorobenzenesulfonate has effectiveness comparable to methadone in suppressing narcotic withdrawal symptoms and in maintenance therapy of narcotic addicted laboratory mammals.

United States Patent 1 1 Havera N-BENZYL-N-[2-PHENYL-2-(4-PHENYL-l-PIPERIDYUETHYL] PROPIONAMIDE PARA-CHLOROBENZENE SULFONATE [75] Inventor:Herbert John Havera, Edwardsburg,

Mich.

[73] Assignee: Miles Laboratories, Inc., Elkhart,

Ind.

[22] Filed: May 24, 1973 21 Appl. No.: 363,425

[51] Int. Cl C07d 29/30 [58] Field of Search 260/293.76, DIG. 13

[56] References Cited UNITED STATES PATENTS 3,518,274 6/1970 Strycker260/293.76

l l Jan. 28, 1975 Primary ExaminerHenry R. Jiles Assistant Examiner-S.D. Winters Attorney, Agent, or Firm-Myron B. Sokolowski; Louis E.Davidson; Joseph C. Schwalbach [57] ABSTRACT 1 Claim, N0 DrawingsBACKGROUND OF THE lNVENTlON 1. Field of the lnvention Treatment ofnarcotic addiction currently involves two overlapping aspects andobjectives: withdrawal of the narcotic and rehabilitation of the addict.in the case of opioid dependence, specifically heroin or morphineaddiction, the treatment of withdrawal symptoms and rehabilitation mergein the concept of maintenance therapy.

Maintenance therapy is a relatively new approach to narcotic addictionpioneered predominantly by Dole and co-workers (Arch. lnt. Med. I18: 304[1966]; J. Am. Med. Assn., 206: 2708 [i968]; and New Engl. J. Med, 280:1372 {l969]). The therapeutic regimen devised by Dole et al. involvesstabilization of narcotic addiets by the oral administration of anarcotic substitute so that the euphoric effects of even high doses ofintravenously administered narcotics are obviated. Oral administrationof the narcotic substitute is of central importance to maintenancetherapy because the psychological extremes which characterize effects ofrepeated intravenously administered narcotics are eliminated. Oralingestion of the narcotic substitute also facilitates supervision ofadministration, thus minimizing the possibility of illicitredistribution of the substitute.

The narcotic substitute most frequently utilized in maintenance therapyis methadone hydrochloride (hereinafter referred to as methadone").Although the use of methadone as a narcotic substitute in maintenancetherapy has been relatively successful, it is po' tentially subject toabuse if administered intravenously to obtain potentiated narcoticeffects.

This invention provides a possible candidate for the suppression ofwithdrawal effects of narcotics and for the maintenance therapy ofaddiction which is effective only upon oral administration.

2. Description of the Prior Art Bochmuhl et al. reported the synthesisand structure of methadone, 6-dimethy|amino-4,4-diphenyl-3- 2 heptanone(Ann, 56]: 52 [1948]). As is evident from its structure,

methadone is chemically unrelated to N-benzyl-N- 5[2-phenyl-2-(4-phenyl-l-piperidyl)- ethyllpropionamidep-chloro-benzene-sulfonate (hereinafter designated as TR 2923).

Strycker (US. Pat. No. 3,518,274 [l970]) disclosed certain congeners ofTR 2923 which are reported as analgetics. Although these congeners arechemically similar to TR 2923, they do not exhibit the unexpectedproperties of TR 2923 in suppressing narcotic withdrawal symptoms orutility in maintenance treatment of narcotic addiction.

I SUMMARY OF THE INVENTION One of the physical chemical properties of TR2923 which is germane to its utility is :its virtual insolubility inwater (less than 0.05%).

Example 1 of the Description of Preferred Embodiments section of thisspecification delineates the total synthesis of TR 2923, which is amodification of the method disclosed by W. G. Strycker in US. Pat. No.3,518,274 (issued June 30, 1970). For purposes of this section, thefollowing sequence of reactions represents a compendium of thissynthesis:

DM F

LiAlH THF hen

zene

In contrast to its congeners, TR 2923, when administered orally,exhibits unexpected utility in suppression of narcotic withdrawal (orabstinence) symptoms and in model maintenance therapy of narcoticaddicted experimental animals. Example 2 of the Description of PreferredEmbodiments section of this specification outlines detailedresults ofthe comparable effectiveness of TR 2923 to the reference drug methadonein suppressing naloxone-precipitated abstinence symptoms in narcoticaddicted rats. Example 2 also demonstrates the utility of TR 2923 as apossible alternate to methadone in the maintenance therapy of narcoticaddiction. For purposes of definition, the term maintenance therapyrefers to the therapeutic concept and regimen developed by Dole andco-workers (see references cited in Field of the Invention, supra).

Like methadone, TR 2923 is effective when orally administered; unlikemethadone, however, TR 2923 cannot be administered intravenously becauseof its insoluble character. As a potential alternate to methadone inmaintenance treatment of narcotic addicts, TR 2923 possesses theadditional advantage that it cannot be abused by intravenousself-administration to obtain potentiated effects. In Example 2 TR 2923was suspended in (W/V) mucilage of acacia. Alternately it can be mixedwith a chocolate paste, or with othe preparations for oral ingestion.

This invention, accordingly, has the following objects:

l. to provide a compound which suppresses narcotic withdrawal symptomsin narcotic addiction; 5

2. to prepare a compound which is a potential alternate to methadone inmaintenance therapy of narcotic addiction; and

. ioc n cu HCH2-CH-N 3. to furnish a compound which has the aboveobjects and which additionally can be administered only orally.

DESCRIPTION OF THE PREFERRED EMBODlMENTS EXAMPLE 1 Synthesis ofN-Benzyl-N-[ 2-Phenyl-2-(4-Phenyll -Piperidyl) EthyllPropionamidePara-Chlorobenzenesulfonate.

A. N-Benzyl-a-Chlorophenylacetamide A benzene solution ofa-chlorophenylacetyl chloride (113.5 g, 0.6 mole) was slowly added to anice-cold, stirred solution of benzylamine (64.4 g, 0.6 mole) in 650 mlof benzene and 200 ml of 20% NaOH. This mixture was stirred in the coldfor an additional hour and subsequently filtered. The solid obtainedfrom the concentration of the filtrate was recrystallized from anaqueous methyl alcohol: yield, g; m.p. 96.597.0.

Analysis: Calculated: C H ClNO: N, 5.39. Found: N, 5.28.

B.- N-Benzyl-2-Phenyl-2-(4-Phenyl-l-Piperidyl) Acetamide.

A mixture of N-benzyl-a-chlorophenylacetamide (62 g, 0.239 mole),4-phenylpiperidine (38.5 g, 0.239 mole), sodium carbonate (28.6 g, 0.27mole) and 350 ml of dimethylformamide was heated under reflux withstirring for 20 hours. The mixture was filtered. The filtrate wasdiluted with methyl alcohol and water, then cooled. The solid thatformed was collected and dried: yield, 73.2 g; m.p. l33l34.

Analysis: Calculated C,,,H,,,N,0= N, 7.29. Found: N, 7.42.

C. N-[2-Phenyl-2-(4-Phenyl-l-Piperidyl)Ethyl] Benzylamine.

A tetrahydrofuran (THF) solution of N-benzyl-Z- phenyl-2-(4-phenyl- I-piperidyl)acetarnide (73 g, 0. l 9 mole) was slowly added to a stirredsuspension of LiAlH 11 g, 0.285 mole) in 150 ml of THF and the mixturewas heated under reflux for 16 hours. The cooled mixture was reactedwith l 1 ml of water in 100 ml of THF (dropwise) followed by 11 ml of20% NaOH, and 33 ml of water. The mixture was filtered and the filtratewas concentrated and distilled: b.p.. 210-218; yield, 46 g.

Analysis: Calculated C 11 N N, 7.56. Found: N, 7.54.

D. N-Benzyl-N-[2-Phenyl-2-(4-Phenyl-l-Piperidyl) EthyllPropionamide.

To 48 g (0.13 mole) ofN-[2-phenyl-2-(4-phenyl-lpiperidyl)ethyl]benzylamide in 150 ml of drybenzene was added 17.0 g (0.13 mole) of propionic anhydride. Thereaction mixture was heated at reflux for 2 hours. The solution wastreated with 200 ml of NaOH and then washed with water. The organiclayer was dried over MgSO and concentrated in vacuo giving an oil whichwas used without an further purification in the preparation of thep-chlorobenzenesulfonate.

E. N-Benzyl-N-[2-Phenyl-2-(4-Phenyll -Piperidyl Ethyl]Propionamidep-Chlorobenzenesulfonate.

To 1.5 g (0.0035 mole) of N-benzyl-N-[2-phenyl-2-(4-phenyl-l-piperidyl)ethyl]propionamide was added 0.7 g (0.0035 mole)of p-chlorobenzenesulfonic acid in 10 ml of CH OH. Upon addition ofether a solid formed. The solid was recrystallized from methyl alcoholand ether: yield, 1.2 g, m.p. 155-l57, solubility 5.2 lO' in water.

Analysis: Calculated C l-l ClN O S: C, 67.89; H, 6.35; N, 4.52. Found:C, 68.39; H, 6.47; N, 4.28.

Example 2 Comparative Effectiveness of Orally Administered Doses ofN-Benzyl-N-[2-Phenyl-2-(4-Phenyl-1-Piperidyl)- Ethyl] PropionamidePara-Chlorobenzenesulfonate (TR 2923) and Methadone in suppressingNarcotic Withdrawal Effects and in Maintenance Therapy of MorphineAddicted Rats It has been demonstrated that narcotic addiction quicklycan be induced in the rat by continuous exposure to morphine (Greenbach,Fed. Proc., 28: 262 [1969]), and that the degree of this addiction canbe assessed by the intensity of abstinence symptoms or by the dose ofnaloxone required to precipitate such symptoms (Way et al.. Science.162: 1290 [1968]). Abstinence effects or withdrawal symptoms in morphineaddicted rats include diarrhea. irritability to handling. chewing,withdrawal jumping, and teeth chattering. A rapid test for the action ofdrugs on addiction in the rat, utilized in this Example, involvesinduction of addiction with a single subcutaneous dose of 150 mg/kg ofmorphine in a sustained release suspension and, 24 hours later,precipitation of withdrawal effects by administration of a subcutaneousdose of naloxone of 1.0 mg/kg (H. O. J. Collier, et al., Nature: 237,220 [1972]. To compare the effects of TR 2923 and methadone in naloxoneprecipitated withdrawal symptoms, varying doses of either drug wereorally administered to the rats.

Methadone HCl or TR 2923 was administered orally in distilled water or asuspension of 20% W/v mucilage of acacia, respectively.

Tables 1 and I1 summarize the results of suppression by oral methadoneHCI or TR 2923 of naloxone precipitated morphine withdrawal symptoms inthe morphine addicted rat. The numerator represents the number of ratsin which a given symptom was observed while the denominator denotes thepopulation of rats involved.

TABLE 1 Drug Treatment Dose in mg No. of Deaths lncidence of WithdrawalEffect 1 h Prior to Base/kg Prior to in Morphine-Dependent Rats NaloxoneP.O. Naloxone Diarrhea lrritability Chewing by 30 Min. to HandlingDistilled 0/6 6/6 4/6 6/6 water Methadone H5 3/4 2/4 l/4* HCI 80 H6 0/5"0/5 1/5* 160 4/5 0/1 0/1 0/1 Acacia 0/8 7/8 7/8 4/8 TR 2923 40 0/8 7/87/8 3/8 80 H6 5/5 3/5 2/5 160 N8 5/7 ll? 2]? Naloxone wan given at l mghate/kg St. indicates significant (P 0.05) suppression of withdrawaleffect compared to controls.

TABLE 11 Drug Dose in No. of Percentage Incidence of Withdrawal EffectTreatment mg base/kg Deaths in Morphine-Dependent Rats l h Prior P.O.Prior to to Naloxone Naloxone Jumping Diarrhea lrritability ChewingTeeth by 15 Min. to touch to handling Chattering Distilled 0/9 78 78 44100 100 100 water Methadone 40 0/10 30 0* 0* 40* 40* HCl A 160 5/10 0*0* 0 20* 40* 0* Acacia 0/12 83 100 8 100 100 TR 2923 40 2/9 78 78 ll 78100 100 Indicates significant (P 0.0S) suppression of withdrawal effectcompared to controls.

Naloxone was given at 1 mg base/kg S.C.

EXAMPLE 3 Suppression of Heroin-Seeking Behavior by TR 2923 inHeroin-Addicted Rats Heroin dependence was induced in two female Wistarrats by the method described by Collier (Endeavor, 31: 123 H9721): Inthe latter procedure the rats were prepared with an indwellingintravenous cannula connected to an infusion pump which was activated bya lever in the wall of a cage containing the rats. By pressing thelever, the rats self-injected the heroin.

The rats had reached a stable level of selfadministration of heroin overa 2 week period (0.25 mg/kg infusion of heroin at a rate of 0.1 ml/lsec.). During this period the rats were fed chocolate paste (3 g/rat)daily at noon. Food pellets were also available ad lib.

Once the rats became dependent on heroin, they were offered TR 2923 inchocolate paste in three dose levels: 10, 40, and 80 mg/kg. and eachtreatment day was separated by 2 days during which chocolate paste alonewas available. Over the 24 hour period following administration of TR2923 orally, self-administration of heroin was reduced. A dose of 10mg/kg of TR 2923 reduced self-administration of heroin by 37.5%; dosesof 40 mg/kg and mg/kg reduced self-administration of heroin by 64.3% and81.1%, respectively. During the period 20-24 hours after oraladministration of 80 mg/kg of TR 2923, one animal beganselfadministration of heroin at a rate equivalent to that prior to oraltreatment. This relapse did not occur until the 28-30 hour period in theother animal. Behavioral effects after administration of TR 2923 in bothrats were similar to those seen after heroin.

What is claimed is:

1. N-benzyl-N-[2-phenyl-2-(4-phenyl-l-piperidyl) ethyl]propionamidep-chlorobenzenesulfonate.

